This proposal is focused on developing a novel mechanism to genetically modify hematopoietic stem cells for use in transplantation in order to increase the frequency of regulatory T cells to ameliorate experimental autoimmune encephalomyelitis, the mouse model of the human disease multiple sclerosis. Several autoimmune diseases, including both multiple sclerosis and diabetes, have been reported to have a deficiency in the number or function of regulatory T cells. The particular regulatory T cell under study is an inducible IL-10-secreting regulatory T cell. It is induced by amino acid copolymers used in the treatment of both experimental autoimmune encephalomyelitis and multiple sclerosis. In brief, the proposal is based on our discovery that the T cell receptor from these cells encodes the information that leads to secretion of the immunosuppressive cytokine IL-10, a novel function for a T cell receptor. The introduction of the gene encoding this T cell receptor into a retrovirus vector that is used to transduce hematopoietic stem and progenitor cells allows for the generation of retrogenic mice that then express high levels of IL-10-secreting T cells. In an initial experiment these mice were protected from an induction of EAE. We propose to extend these studies on protection and to investigate its mechanism and durability. The technique represents a novel way of altering the lymphocyte repertoire in a beneficial manner. The procedure may be adaptable to man, and, if so, could provide a permanent protection from relapses in multiple sclerosis and other autoimmune diseases.